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      Lactate administration activates the ERK1/2, mTORC1, and AMPK pathways differentially according to skeletal muscle type in mouse

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          Abstract

          Skeletal muscle is described as an endocrine organ, constitutively or intermittently secreting bioactive molecules. The signaling pathways by which these molecules mediate changes in skeletal muscle and regulate interorgan crosstalk are only partly understood. Lactate is widely described as a signaling molecule in different cells, but the role of lactate as a signaling molecule in mature skeletal muscle has not been fully unveiled. The aim of this study was to determine the role of lactate on activation of signaling pathways in adult mouse skeletal muscle. Male mice were injected intraperitoneally with lactate or saline, and tissues were dissected after 40 min. Phosphorylation levels of relevant proteins in muscle were assessed by Western blotting. After lactate administration, we found an increase in p‐ ERK1/2 Thr202/Tyr204 (3.5‐fold; P = 0.004) and p‐p70S6 K T hr389 (1.9‐fold; P = 0.01) in quadriceps; and an increase in p‐rpS6 Ser235/236 in both quadriceps (6.3‐fold; P = 0.01) and EDL (2.3‐fold; P = 0.01), without changes in soleus. There was a tendency toward an increase in p‐ AMPK T hr172 (1.7‐fold; P = 0.08), with a significant increase in p‐ ACC S er79 (1.5‐fold; P = 0.04) in soleus, without changes in quadriceps and EDL. These results support the hypothesis that lactate plays a role in the molecular signaling related to hypertrophy and to oxidative metabolism on adult skeletal muscle and suggest that this activation depends on the skeletal muscle type. The mechanisms that underlie the effect of lactate in mature skeletal muscles remain to be established.

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          Muscles and their myokines.

          In the past, the role of physical activity as a life-style modulating factor has been considered as that of a tool to balance energy intake. Although it is important to avoid obesity, physical inactivity should be discussed in a much broader context. There is accumulating epidemiological evidence that a physically active life plays an independent role in the protection against type 2 diabetes, cardiovascular diseases, cancer, dementia and even depression. For most of the last century, researchers sought a link between muscle contraction and humoral changes in the form of an 'exercise factor', which could be released from skeletal muscle during contraction and mediate some of the exercise-induced metabolic changes in other organs such as the liver and the adipose tissue. We have suggested that cytokines or other peptides that are produced, expressed and released by muscle fibres and exert autocrine, paracrine or endocrine effects should be classified as 'myokines'. Given that skeletal muscle is the largest organ in the human body, our discovery that contracting skeletal muscle secretes proteins sets a novel paradigm: skeletal muscle is an endocrine organ producing and releasing myokines, which work in a hormone-like fashion, exerting specific endocrine effects on other organs. Other myokines work via paracrine mechanisms, exerting local effects on signalling pathways involved in muscle metabolism. It has been suggested that myokines may contribute to exercise-induced protection against several chronic diseases.
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            Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons.

            L-lactate is a product of aerobic glycolysis that can be used by neurons as an energy substrate. Here we report that in neurons L-lactate stimulates the expression of synaptic plasticity-related genes such as Arc, c-Fos, and Zif268 through a mechanism involving NMDA receptor activity and its downstream signaling cascade Erk1/2. L-lactate potentiates NMDA receptor-mediated currents and the ensuing increase in intracellular calcium. In parallel to this, L-lactate increases intracellular levels of NADH, thereby modulating the redox state of neurons. NADH mimics all of the effects of L-lactate on NMDA signaling, pointing to NADH increase as a primary mediator of L-lactate effects. The induction of plasticity genes is observed both in mouse primary neurons in culture and in vivo in the mouse sensory-motor cortex. These results provide insights for the understanding of the molecular mechanisms underlying the critical role of astrocyte-derived L-lactate in long-term memory and long-term potentiation in vivo. This set of data reveals a previously unidentified action of L-lactate as a signaling molecule for neuronal plasticity.
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              Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81.

              Lactic acid is a well known metabolic by-product of intense exercise, particularly under anaerobic conditions. Lactate is also a key source of energy and an important metabolic substrate, and it has also been hypothesized to be a signaling molecule directing metabolic activity. Here we show that GPR81, an orphan G-protein-coupled receptor highly expressed in fat, is in fact a sensor for lactate. Lactate activates GPR81 in its physiological concentration range of 1-20 mM and suppresses lipolysis in mouse, rat, and human adipocytes as well as in differentiated 3T3-L1 cells. Adipocytes from GPR81-deficient mice lack an antilipolytic response to lactate but are responsive to other antilipolytic agents. Lactate specifically induces internalization of GPR81 after receptor activation. Site-directed mutagenesis of GPR81 coupled with homology modeling demonstrates that classically conserved key residues in the transmembrane binding domains are responsible for interacting with lactate. Our results indicate that lactate suppresses lipolysis in adipose tissue through a direct activation of GPR81. GPR81 may thus be an attractive target for the treatment of dyslipidemia and other metabolic disorders.
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                Author and article information

                Contributors
                pllanos@odontologia.uchile.cl
                ejaimovi@med.uchile.cl
                Journal
                Physiol Rep
                Physiol Rep
                10.1002/(ISSN)2051-817X
                PHY2
                physreports
                Physiological Reports
                John Wiley and Sons Inc. (Hoboken )
                2051-817X
                19 September 2018
                September 2018
                : 6
                : 18 ( doiID: 10.1002/phy2.2018.6.issue-18 )
                : e13800
                Affiliations
                [ 1 ] Faculty of Medicine Center for Exercise, Metabolism and Cancer ICBM Universidad de Chile Santiago Chile
                [ 2 ] Laboratory of Exercise Science Clínica MEDS Santiago Chile
                [ 3 ] Department of Nutrition, Exercise and Sports Molecular Physiology Group Faculty of Science University of Copenhagen Copenhagen Denmark
                [ 4 ] Physiology and Biophysics Program ICBM Faculty of Medicine Universidad de Chile Santiago Chile
                [ 5 ] Institute for Research in Dental Sciences Facultad de Odontología Universidad de Chile Santiago Chile
                Author notes
                [*] [* ] Correspondence

                Paola Llanos, Institute for Research in Dental Sciences, Facultad de Odontología, Universidad de Chile, Sergio Livingstone Pohlhammer 943, 8380492 Santiago, Chile.

                Tel: +56 229‐786‐601

                Fax: +56 227‐779‐724

                E‐mail: pllanos@ 123456odontologia.uchile.cl

                and

                Enrique Jaimovich, Center for Exercise, Metabolism and Cancer, ICBM, Faculty of Medicine, Universidad de Chile, 8380453 Santiago, Chile.

                Tel: +56 227‐986‐311

                Fax: +56 227‐776‐916

                E‐mail: ejaimovi@ 123456med.uchile.cl

                Article
                PHY213800
                10.14814/phy2.13800
                6144450
                30230254
                7efbdadc-f2e3-48b5-87a2-4c48b6d33ff7
                © 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 18 June 2018
                : 25 June 2018
                Page count
                Figures: 4, Tables: 0, Pages: 9, Words: 4601
                Funding
                Funded by: Comisión Nacional de Investigación Científica y Tecnológica
                Award ID: T7816110004
                Funded by: Fondo Nacional de Desarrollo Científico y Tecnológico
                Award ID: 11150243
                Award ID: 1151293
                Funded by: Novo Nordisk Foundation Excellence project grant
                Award ID: 15182
                Funded by: Universidad de Chile
                Award ID: UCH‐1566
                Categories
                Signalling Pathways
                Muscle Metabolism
                Skeletal Muscle
                Original Research
                Original Research
                Custom metadata
                2.0
                phy213800
                September 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.9 mode:remove_FC converted:19.09.2018

                metabolism,molecular signaling,skeletal muscle
                metabolism, molecular signaling, skeletal muscle

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